Discovery and development of brain-penetrant ^(18)F-labeled radioligands for neuroimaging of the sigma-2 receptors  

作　　者：Ying Zhang Tao Wang Xiaojun Zhang Winnie Deuther-Conrad Hualong Fu Mengchao Cui Jinming Zhang Peter Brust Yiyun Huang Hongmei Jia 

机构地区：[1]Key Laboratory of Radiopharmaceuticals(Beijing Normal University),Ministry of Education,College of Chemistry,Beijing Normal University,Beijing 100B75,China [2]Nuclear Medicine Department,Chinese PLA General Hospital,Beijing 100853,China [3]Helmholtz-Zentrum Dresden-Rossendorf,Institute of Radiopharmaceutical Cancer Research,Department of Neuroradiopharmaceuticals,Leipzig 04318,Germany [4]PET Center,Department of Radiology and Biomedical Imaging,Yale University School of Medicine,CT 06520-8048,USA [5]The Lübeck Institute of Experimental Dermatology,University Medical Center Schleswig-Holstein,Lubeck 23538,Germany

出　　处：《Acta Pharmaceutica Sinica B》2022年第3期1406-1415,共10页药学学报（英文版）

基　　金：supported by the National Natural Science Foundation of China(No.21876013);Beijing Natural Science Foundation(7212203,China)。

摘　　要：We have discovered and synthesized a series of indole-based derivatives as novel sigma-2(σ_(2))receptor ligands.Two ligands with high σ_(2) receptor affinity and subtype selectivity were then radiolabeled with F-18 in good radiochemical yields and purities,and evaluated in rodents.In biodistribution studies in male ICR mice,radioligand[18F]9,or 1-(4-(5,6-dimethoxyisoindolin-2-yl)butyl)-4-(2-[18F]fluoroethoxy)-1H-indole,was found to display high brain uptake and high brain-to-blood ratio.Pretreatment of animals with the selective σ_(2) receptor ligand CM398 led to significant reductions in both brain uptake(29%-54%)and brain-to-blood ratio(60%-88%)of the radioligand in a dose-dependent manner,indicating high and saturable specific binding of[18F]9 to σ_(2) receptors in the brain.Further,ex vivo autoradiography in male ICR mice demonstrated regionally heterogeneous specific binding of[18F]9 in the brain that is consistent with the distribution pattern of σ_(2) receptors.Dynamic positron emission tomography imaging confirmed regionally distinct distribution and high levels of specific binding for[18F]9 in the rat brain,along with appropriate tissue kinetics.Taken together,results from our current study indicated the novel radioligand[18F]9 as the first highly specific and promising imaging agent for σ_(2) receptors in the brain.

关 键 词：Indole-based derivatives σ2 receptor FLUORINE-18 Positron emission tomography NEUROIMAGING 

分 类 号：R914.5[医药卫生—药物化学]